The transdermal absorption preparations which are now put into a practical use or under development can be roughly classified from the standpoint of storage and release of drugs into (1) a reservoir type, (2) a matrix type, (3) a pressure-sensitive adhesive (autohesion) tape, (4) a multilayer adhesive tape, and (5) others. Each of the drug-storing layers uses, as a base thereof, a silicone oil in (1), a hydrophilic polymer such as polyvinylalcohol (PVA), polyvinylpyrrolidone (PVP), etc., or a silicone elastomer in (2), and an acrylate type adhesive (PSA) in (3). The above-described (4) includes a preparation in which adhesive layers having different affinities to the drug are overlaid in a multilayer so as to control a releasing property. In addition, various polymers such as a natural rubber, synthetic rubbers, celluloses, synthetic resins, etc. are investigated, but they are presently not put into a practical use.
The purpose of ordinary transdermal absorption preparations is to naturally diffuse the drug in the base and to distribute and transfer the drug to the skin side and allow the drug to be absorbed by the living body upon merely adhering the preparation to the skin surface by utilizing the concentration gradient of the drug as a driving power for the diffusion and release without depending upon a method of applying an external energy such as electricity or ultrasonic wave. Thus, the use of the ordinary transdermal absorption preparation is convenient. In order to achieve the above purpose, it is necessary that the base has at least the following chemical and morphological characteristics.
(a) The base and the drug are required to have an appropriate affinity (compatibility). The term "appropriate" used herein means that the affinity is such a degree that the drug is capable of leaving the base and transferring to the skin. The releasing ratio of the drug varies remarkably depending upon the above affinity, and also the 0 order release is obtainable.
(b) The base is required to be a liquid at ordinary temperatures or, apparently, to be in an intermediate form between solid and liquid states such as a swollen gel which is a liquid-containing form, so that the drug (in particular, a solid drug) can diffuse in the base. In the reservoir type practically used, a silicone oil which is a liquid is used, and in the matrix type, a hydrogel of a water-soluble polymer is used. Also, when a silicone elastomer which is a rubbery polymer is used, the drug is dispersed therein together with a solvent. In the case of an adhesive tape, a tackifier is dispersed as a liquid in an adhesive, and the adhesive per se is a gel which is in an intermediate region between solid and liquid forms. These facts satisfy the above-described requirements of the base.
However, the type wherein the drug is supported in the adhesive does not generally have a relatively high releasing ratio of the drug. Also, although an oily or aqueous swollen gel has the releasing ratio slightly higher than that of the above type, some drugs may have problems in the storage stability when a preparation is produced by using the swollen gel. More specifically, there are possibility of changes in the initial dose of the drug due to release of a solvent or water as a swelling medium with the passage of time, as well as the modification of the drug by a reaction with a dispersing medium. Further, in the case of the reservoir type wherein a liquid drug is blended in a liquid with a powdery material such as an emulsifying base, or wherein a solid drug is dispersed together with a liquid co-solvent, these components tend to transfer to the surface of the preparation during storage and hence it is unavoidable that the drug accumulates at a high concentration in the release-controlling membrane, and there may be a problem that the drug is drastically released at the initial stage of the application.
(c) The base is required to have a low irritation to the skin or substantially no irritation. Since the plaster is generally replaced repeatedly, a skin inflammation causes a great problem. Thus, reduction in the size of the preparation is advantageous.
(d) Even if the drug takes effect with only a small dose of several micrograms and is unstable such that the drug is easily modified by air, moisture, heat, or the like, it is necessary that the drug can be stored stably and released at a high releasing ratio. The drug of which formulation into a transdermal absorption preparation is particularly significant is those having a high decomposition ratio in the digestive tract, liver, etc., a short half-life and a low effective serum concentration. Most of these drugs have the above-described characteristics and hence it is necessary to take any countermeasure thereto.
(e) Even if the drug is water-soluble and has poor permeability and absorption through the skin, it is necessary that the drug can be slowly released into the body at a high efficiency. It is desirable that the above can be achieved, in particular, without using an absorption enhancer, etc. Recently, studies on the absorption enhancer have been made extensively, but troublesome issues are involved therein such as the necessity of investigation on the toxicity of the enhancer itself.
For solving the above-described problems, the present inventors developed the base polymers described in JP-A-63-108019 and JP-A-63-146812 (The term "JP-A" as used herein means an unexamined published Japanese patent application.). That is, the base polymer is a heat-sensitive and water-sensitive amphipathic polymer which is a segment polyurethane in which block linkages are adjusted in such a manner that the hydrophilicity increases as the block comes close to one end of the polymer molecule and the hydrophobicity or lipophilicity increases as the block comes close to other end of the polymer molecule.
In the above amphipathic polymer compound, a balance of hydrophilicity and the hydrophobicity and a molecular weight of constituting molecules of the segments are adjusted so that the polymer can dissolve or melt in response to water or heat. When it is dissolved or molten, the hydrophilic segment solubilizes a hydrophilic drug and the hydrophobic (lipophilic) segment solubilizes a hydrophobic (lipophilic) drug. Generally, drugs have a structure containing polar groups or non-polar groups and have hydrophilic, lipophilic or amphipathic characteristics and is dissolved in the same type of solvents. Even if the drug is exceptionally insoluble in solvents, the drug takes effect as long as it is dissolved in a very minute amount and, therefore, the drug may be investigated at a level of a very low solubility. Accordingly, the drug is necessarily assigned to any of the above-described hydrophilic, lipophilic and amphipathic groupings. Also, since the solubilization by this polymer makes it possible to dissolve the drug at a molecular level, i.e., as a molecular dispersion, it is particularly effective for slow-releasing of a physiologically active material which takes effect with a very minute dose of several micrograms per prescription. In other word, in order to store a drug which has a low effective serum concentration and which takes effect with a very minute dose and to release the drug, dispersion of the drug at a molecular level is essential. Most of these physiologically active materials are also easily decomposed by oxygen, water, heat, etc. However, as the term "heat-sensitive property" connotes, the polymer keeps a solid state at ordinary temperatures below 30.degree. C. and hence the drug can be stably maintained in a solid. When applied to the surface of a living body, the polymer is easily transformed from a solid to a liquid by sharply responding to the temperature of the body surface. Also, the polymer is dissolved by a small amount of water exuded from the body surface, and the drug is diffused and transferred in the polymer. Although some drugs are in a liquid state at ordinary temperatures, most of drugs are in a solid state. In order to release a solid drug by diffusion in a base and to absorb the drug into the skin, the base must be either a liquid or a gel material. The above-mentioned polymer satisfies this requirement and can be used as a base polymer for a transdermal absorption preparation applicable to many drugs.
However, as a result of further studies, the present inventors found that a heat-sensitive polymer having a higher hydrophilicity is required for, among others, hydrophilic drugs which are difficult to be absorbed by and permeate into the skin. Also, it has been found that, in order to release these drugs efficiently within a short period of time, for example, a predetermined time of from 24 to 48 hours, the dissolved and molten polymer is required to have a lower viscosity and form an environment in which the drug is easily diffused. The present invention was completed in the light of such a demand.